Chemistry:Pitolisant

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Short description: Medication to treat narcolepsy
Pitolisant
Pitolisant skeletal.svg
Clinical data
Pronunciation/pɪˈtɒlɪsənt/
pi-TOL-i-sənt
Trade namesWakix, Ozawade
Other namesTiprolisant; Ciproxidine; BF2.649
AHFS/Drugs.comMonograph
MedlinePlusa619055
License data
Routes of
administration		By mouth
Drug classHistamine H3 receptor inverse agonists
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H26ClNO
Molar mass295.85 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy.[2] It is a histamine 3 (H3) receptor antagonist/inverse agonist (an antihistamine drug specific to that kind of receptors).[2] It represents the first commercially available medication in its class, so that the US Food and Drug Administration (FDA) declares it a first-in-class medication.[6][7] Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.[8]

The most common side effects include difficulty sleeping, nausea, and feeling worried.[9]

Medical uses

Pitolisant is indicated in adults for the treatment of narcolepsy.[2][3] Narcolepsy is a chronic sleep disorder that causes overwhelming daytime drowsiness.[3] Pitolisant is also indicated to improve alertness and reduce excessive daytime sleepiness in adults with obstructive sleep apnea.[4]

Side effects

The most common side effects include insomnia, headache, nausea, anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo, and dyspepsia (heartburn).[3] Rare but serious side effects are abnormal loss of weight and spontaneous abortion.[3]

Pharmacology

Pitolisant is an inverse agonist of the histamine 3 (H3) autoreceptor. The H3 autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine synthesis and release upon binding to endogenous histamine.[10] By preventing the binding of endogenous histamine at the H3, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.[11]

Pitolisant is a drug that belongs to the class of CNS stimulants.[12][13][14][15] Pitolisant is also considered a medication of class "eugeroic", which means that it promotes wakefulness and alertness. Eugeroics are different from traditional CNS stimulants such as amphetamine in that they have fewer side effects and lower abuse potential. Pitolisant is the first eugeroic drug that acts by blocking the histamine 3 (H3) autoreceptor, which increases the activity of histamine neurons in the brain. Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.[16][17][18]

History

Pitolisant is marketed in the European Union by Bioprojet Pharma.[3] It was approved for medical use in the European Union in March 2016.[3]

The US Food and Drug Administration (FDA) approved pitolisant for excessive daytime sleepiness in participants with narcolepsy based primarily on evidence from two trials (Trial 1/NCT01067222, Trial 2/NCT01638403).[9] An additional trial (Trial 3/NCT01800045), in which participants with a different type of narcolepsy were exposed to the same dose of pitolisant, was used to add data for evaluation of side effects.[9] The trials were conducted in Europe and South America.[9]

The two primary trials enrolled adults with narcolepsy and excessive daytime sleepiness.[9] Participants received pitolisant, placebo, or an approved drug for narcolepsy for eight weeks.[9] For participants receiving pitolisant, the dose could be increased during the first three weeks but had to remain the same for the next five weeks.[9] Neither the participants nor the healthcare providers knew which treatment was being given during the trial.[9]

The benefit of pitolisant was evaluated by comparing changes in daytime sleepiness during the trial between pitolisant- and placebo-treated participants.[9] To measure the daytime sleepiness, the investigators used a scale called the Epworth Sleepiness Scale (ESS).[9] The ESS asks participants to rate the likelihood that they would fall asleep while doing eight daily activities (such as sitting and reading or watching television).[9] Participants rate each item from zero (would never doze) to three (high chance of dozing).[9]

Pitolisant was approved by the FDA in August 2019.[9] It was granted orphan drug designation for the treatment of narcolepsy,[19] fast track designation for the treatment of excessive daytime sleepiness and cataplexy in people with narcolepsy, and breakthrough therapy designation for the treatment of cataplexy in people with narcolepsy.[20]

Society and culture

Legal status

Pitolisant is approved in the European Union and the United States to treat narcolepsy, and is not a controlled substance in these countries.[failed verification] Still, long-term studies comparing the effectiveness and tolerability of pitolisant with modafinil or sodium oxybate are lacking.[failed verification] Pitolisant, the only non-controlled anti-narcoleptic drug in the US,[18] has shown minimal abuse risk in studies.[18][21]

References

  1. ↑ "Summary Basis of Decision (SBD) for Wakix". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00550&lang=en. 
  2. ↑ 2.0 2.1 2.2 2.3 "Wakix- pitolisant hydrochloride tablet, film coated". 6 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8daa5562-824e-476c-9652-26ceef3d4b0e. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Wakix EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/wakix.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ 4.0 4.1 "Ozawade EPAR". 20 May 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade. 
  5. ↑ "Ozawade Product information". https://ec.europa.eu/health/documents/community-register/html/h1546.htm. 
  6. ↑ "New Drug Therapy Approvals 2019". 31 December 2019. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019. 
  7. ↑ "FDA Approves Pitolisant for Daytime Sleepiness in Patients with Narcolepsy". 16 August 2019. https://www.pharmacytimes.com/news/fda-approves-pitolisant-for-daytime-sleepiness-in-patients-with-narcolepsy. 
  8. ↑ "Pitolisant: First Global Approval". Drugs 76 (13): 1313–1318. September 2016. doi:10.1007/s40265-016-0620-1. PMID 27438291. 
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 "Drug Trials Snapshots: Wakix". 14 August 2019. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-wakix.  This article incorporates text from this source, which is in the public domain.
  10. ↑ "Identification of two H3-histamine receptor subtypes". Molecular Pharmacology 38 (5): 610–613. November 1990. PMID 2172771. https://molpharm.aspetjournals.org/content/38/5/610. 
  11. ↑ "pitolisant, a novel histamine-3 receptor competitive antagonist, and inverse agonist, in the treatment of excessive daytime sleepiness in adult patients with narcolepsy". Health Psychology Research 10 (3): 34222. 30 May 2022. doi:10.52965/001c.34222. PMID 35774905. 
  12. ↑ "Pitolisant". National Institute of Diabetes and Digestive and Kidney Diseases. 2012. https://www.ncbi.nlm.nih.gov/books/NBK573784/. 
  13. ↑ "Central Nervous System (CNS) Stimulants". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 22 January 2012. http://www.ncbi.nlm.nih.gov/books/NBK548702/. 
  14. ↑ "Pitolisant Uses, Side Effects & Warnings". https://www.drugs.com/mtm/pitolisant.html. 
  15. ↑ "List of CNS stimulants + Uses & Side Effects". https://www.drugs.com/drug-class/cns-stimulants.html. 
  16. ↑ "Pitolisant (Wakix) for Narcolepsy". JAMA 326 (11): 1060–1061. 21 September 2021. doi:10.1001/jama.2021.1349. PMID 34546302. https://doi.org/10.1001/jama.2021.1349. 
  17. ↑ "The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use". Sleep Medicine 33: 125–129. 1 May 2017. doi:10.1016/j.sleep.2017.01.002. PMID 28449891. https://doi.org/10.1016/j.sleep.2017.01.002. 
  18. ↑ 18.0 18.1 18.2 "Pitolisant: A Review in Narcolepsy with or without Cataplexy". CNS Drugs 34 (2): 207–218. February 2020. doi:10.1007/s40263-020-00703-x. PMID 31997137. 
  19. ↑ "Pitolisant Orphan Drug Designations and Approvals". 17 May 2010. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=307210. 
  20. ↑ "Harmony's pitolisant granted breakthrough and fast track designations". 22 May 2018. https://www.pbiforum.net/mag/featured/harmonys-pitolisant-granted-breakthrough-and-fast-track-designations/. 
  21. ↑ "Evaluating pitolisant as a narcolepsy treatment option". Expert Opinion on Pharmacotherapy 22 (2): 155–162. February 2021. doi:10.1080/14656566.2020.1817387. PMID 32941089. 

External links

  • Clinical trial number NCT01067222 for "Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy (Harmony1)" at ClinicalTrials.gov
  • Clinical trial number NCT01638403 for "Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy." at ClinicalTrials.gov



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